We have shown that plasmid constructs containing HIV env and rev genes are safe and immunogenic when administered to HIV-infected and HIV-naive subjects. We hypothesize that the use of this vaccine combined with a gag/pol construct will be safe and more stimulatory of HIV-1-specific immune responses in HIV-naive subjects than the env/rev vaccine alone. We further hypothesize that combining the optimal dose of the two HIV vaccines with a construct containing the gene for an immunostimulatory molecule such as IL-12 or B7-2 will enhance responses to the HIV vaccines. We propose a total of 3 clinical trials to test these hypotheses. First, we will perform a dose-escalation trial of the combined gag/pol and env/rev vaccines to determine optimal dose for safety and immune response. Second, we will compare the adjuvant effects of constructs containing either the IL-12 or B7-2 genes when co-administered with the optimized dose of the combined HIV vaccines. Finally, we will compare the more effective of the adjuvant constructs from trial 2 versus several additional immunostimulatory gene constructs derived from Projects 1 and 2 of this Proposal, to determine if any of the new products have a better adjuvant effect for the combined HIV vaccines. The long-term goal of the proposed research is to determine the optimal doses of the HIV-1 vaccines to be administered with the most effective adjuvant vaccine to employ in a large field trial of prophylactic efficacy and safety in HIV-naive subjects at risk of infection.